The liver displays a unique ability to grow and regenerate. For example, complete hepatic regeneration[unreadable] occurs within days to weeks after two-thirds of the liver has been resected. Chronic hepatocellular damage[unreadable] can lead to impaired regulation of regeneration, which results in hepatocellular carcinoma, one of the most[unreadable] common malignancies in the world. Despite the clinical significance of this topic, fundamental questions[unreadable] remain. Growth factors stimulate liver regeneration by activation of receptor tyrosine kinases, which in turn[unreadable] increases free Ca2+ within the cytosol and nucleus, but the relative role of cytosolic and nuclear Ca2+ in the[unreadable] regulation of liver growth is unclear. However, we now know that changes in both nuclear and cytosolic Ca2[unreadable] + in hepatocytes are mediated by inositol 1,4,5-trisphosphate (InsPS), and that distinct InsPS receptors[unreadable] (InsPSRs) within the nucleus are capable of locally increasing Ca2+. Furthermore, nuclear Ca2+ is[unreadable] important for growth factor-mediated gene expression. Based on these findings, Project by Nathanson will test the[unreadable] hypothesis that receptor tyrosine kinases regulate cell growth by inducing lnsP3-mediated Ca2+ signals[unreadable] within the nucleus. The hepatocyte growth factor (HGF) receptor will be used as a model to test this[unreadable] hypothesis through three specific aims:[unreadable] 1. The mechanism by which the phosphorylated HGF receptor reaches the nucleus will be determined.[unreadable] 2. The mechanism by which the nuclear HGF receptor locally generates InsPS and thus nuclear calcium[unreadable] signals will be identified.[unreadable] 3. The process through which nuclear Ca2+ regulates cell growth will be examined.[unreadable] These studies will reveal how growth factors and their corresponding receptor tyrosine kinases control[unreadable] nuclear Ca2+ in intact cells, and identify the distinct role this may play in regulating the growth and function[unreadable] of the liver. Together with Projects by Ehrlich and Bennett, this work should provide an integrated understanding of how[unreadable] growth factors act through mitogen-activated protein kinase (MAPK) and MAPK-specific phosphatases to[unreadable] regulate the growth of hepatocytes through Ca2+ signaling within the nucleus.